Ophthalmic drug delivery

ABSTRACT

The present invention includes and provides a method of delivering a medicament to an eye of a subject in need thereof a solution, the method comprising: (a) providing droplets containing the medicament with a specified average size and average initial ejecting velocity; and (b) delivering the medicament to the eye, where the droplets deliver a percentage of the ejected mass of the droplets to the eye.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No. 17/091,607 filed Nov. 6, 2020, allowed, which is a continuation of U.S. application Ser. No. 16/113,231 filed Aug. 27, 2018, issued as U.S. Pat. No. 10,839,960, which is a continuation of U.S. application Ser. No. 15/459,529 filed Mar. 15, 2017 issued as U.S. Pat. No. 10,073,949, which is a continuation of U.S. application Ser. No. 14/793,895 filed Jul. 8, 2015, abandoned, which is a continuation of U.S. application Ser. No. 13/184,446 filed Jul. 15, 2011, issued as U.S. Pat. No. 9,087,145, which claims the benefit of the filing date of U.S. Provisional Application No. 61/400,864 filed Jul. 15, 2010, U.S. Provisional Application No. 61/401,850 filed Aug. 20, 2010, U.S. Provisional Application No. 61/401,920 filed Aug. 20, 2010, U.S. Provisional Application No. 61/401,918 filed Aug. 20,2010, U.S. Provisional Application No. 61/401,848 filed Aug. 20, 2010, U.S. Provisional Application No. 61/401,849 filed Aug. 20, 2010, U.S. Provisional Application No. 61/462,576 filed Feb. 4, 2011, U.S. Provisional Application No. 61/462,791 filed Feb. 5, 2011, U.S. Provisional Application No. 61/463,280 filed Feb. 15, 2011, U.S. Provisional Application No. 61/516,462, filed Apr. 4, 2011, U.S. Provisional Application No. 61/516,496 filed Apr. 4, 2011, U.S. Provisional Application No. 61/516,495 filed Apr. 4, 2011, and U.S. Provisional Application No. 61/516,694, filed Apr. 6, 2011, the entire contents of each of which is specifically hereby incorporated by reference for all purposes. The present application is also related to U.S. Provisional Application No. 61/396,531 filed May 28, 2010, the entire contents of which is specifically hereby incorporated by reference for all purposes.

FIELD OF THE INVENTION

The present invention relates to devices for the generation of ejected droplets, methods of administration and uses thereof, and medicament compositions formulated therefor.

BACKGROUND OF THE INVENTION

A typical medical droplet as dispensed by an eye dropper bottle can vary, depending on the viscosity and surface tension of the fluid. In order to control the amount of active ingredient that is administered in a single droplet, the concentration of the active ingredient is adjusted by volume. Once the concentration is defined, a correct dosage may require one drop or more. However, since the human eye can typically retain only 7 μl of fluid at a time, even a single medical droplet can result in overflow and loss of part of the medication from the eye. Multiple drop dosage often compounds the problem of medication retention in the eye. Subjects will typically administer all droplets required for a dosage in one sitting, which exacerbates the problem and can result in 50 to 90% of the medication overflowing and leaking out of the eye.

Another further problem is that a single droplet of the defined concentration marks the lower limit of a dose and, as such, the amount of active ingredient that can be administered at the defined concentration. For example, pediatric application where lower doses are often advisable are an illustration of where the size/dose of a droplet can be problematic.

Given the above and other limitations of current ophthalmic delivery, a need exists for an efficient delivery system for solutions to the eye, including solutions containing medicaments.

SUMMARY OF THE INVENTION

To address such needs and others, provided herein are stable medicament compositions and uses thereof.

One embodiment provides a method of delivering a medicament to an eye of a subject in need thereof a solution, the method comprising: (a) providing droplets containing the medicament, where said droplets have an average drop size of between about 15 microns and about 100 microns in diameters and an average ejecting velocity of between about 0.5 m/s to about 20 m/s; and (b) delivering the medicament to the eye, where between about 80% to about 100% of the ejected mass of the droplets are deposited on the eye.

Another embodiment provides a method of delivering a medicament solution to a subject in need thereof by controlling droplet size and droplet deposit parameters of the medicament solution, the method comprising: (a) determining desired dosage of the medicament solution for the subject in need thereof; and (b) providing the desired dosage in a single application by determining the droplet size and deposit parameters.

Yet another embodiment provides a method for providing a solution to the eye, the method comprising: (a) providing droplets containing the medicament, having an average droplet size of between about 15 microns and about 100 microns in diameter and an average initial ejecting velocity of between about 0.5 m/s to about 20 m/s; and (b) delivering the medicament to the eye, where between about 80% to about 100% of the ejected mass of the droplets are deposited on the eye.

These and other aspects of the invention will become apparent to one of skill in the art.

DETAILED DESCRIPTION OF THE INVENTION Methods of Generating Ejected Droplets

The present invention provides an effective approach to undertake dosing strategies. Dosing strategies also will incorporate various approaches to initiating treatment, stopping treatment, switching treatment and responding to different subject states.

Examples of dosing modes or strategies include night time administration, administration before waking, increased administration one week a month, three times a day, continuous dosing, bolus dosing, taper dosing, need-based dosing, and feedback dosing by the physician, provider, subject or family. The clinical scenarios where these can be employed include chronic disease, disease exacerbation, need for suppression treatment, need for recurrence treatment, or state of treatment like medicament tolerance.

Methods of Delivery and Treatment

Provided is a method of delivering a medicament to an eye of a subject in need thereof a solution, the method comprising: (a) providing droplets containing the medicament with a specified average size and average initial ejecting velocity; and (b) delivering the medicament to the eye, where the droplets deliver a percentage of the ejected mass of the droplets to the eye.

Devices capable of providing and delivering a fluid such as ophthalmic fluid to the eye are provided. In certain aspects, ejection devices include an ejection assembly which generates or provides a controllable stream of droplets of fluid. Fluids include, without limitation, suspensions and emulsions which have viscosity in a range capable of droplet formation using an ejector mechanism. As explained in further detail herein, in accordance with certain aspects of the present disclosure, the actuator mechanism may form a directed stream of droplets, which may be directed toward a target. The droplets will be formed in distribution of sizes, each distribution having an average droplet size. The average droplet size may be in the range of about 15 microns to about 100 microns, about 20 microns to about 100 microns, greater than 20 microns to about 100 microns, about 20 microns to about 80 microns, about 25 microns to about 75 microns, about 30 microns to about 60 microns, about 35 microns to about 55 microns, etc. However, the average droplet size may be as large as 2500 microns, depending on the intended application. Further, the droplets may have an average initial ejecting velocity of about 0.5 m/s to about 20 m/s, e.g., about 1 m/s to about 10 m/s, about 1 m/s to about 5 m/s, about 1 m/s to about 4 m/s, about 2 m/s, etc. As used herein, the ejecting size and the ejecting initial velocity are the size and velocity of the droplets when the droplets leave the ejector plate. The stream of droplets directed at a target will result in deposition of a percentage of the mass of the droplets including their composition onto the desired location.

The disclosed technology will eject droplets without substantial evaporation, entrainment of air, or deflection off the eye surface, which facilitates consistent dosing. Average ejecting droplet size and average initial ejecting velocity are dependent on factors including fluid viscosity, surface tension, ejector plate properties, geometry, and dimensions, as well as operating parameters of the piezoelectric actuator including its drive frequency. In some implementations, about 60% to about 100%, about 65% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, etc., of the ejected mass of droplets are deposited on the surface of the eye, such deposition being repeatable independent of operating and use conditions. The direction of flow of the stream of droplets may be horizontal, or any direction a user chooses to aim the actuation mechanism during use.

Droplet performance is generally related to particle diameter. Without intending to be limited, ejected droplets are slowed to a stop by air drag (i.e., stopping distance of the ejected droplets). Ejected droplets also fall vertically due to gravity. After a short acceleration time, the droplets reach terminal velocity where the drag force equals the force of gravity. The ejected droplets may carry air along with them, which creates an entrained airstream, which aids to then carry the ejected droplets beyond the calculated stopping distance. However, increased levels of entrained air may cause the ejected droplets to flow across an impact surface (e.g., an eye surface) because the entrained airflow must turn 90 degrees at such a surface. Small, ejected droplets (e.g., droplets having an average diameter less than about 17 microns, less than about 15 microns, etc.) are carried along the surface of the eye by the airstream and may not impact the surface. Contrasted to this, larger ejected droplets create less entrained air than an equivalent mass of smaller droplets, and have enough momentum to impact the surface. The ejected droplet stopping distance is a measure of this effect.

Also provided is a method of delivering a medicament solution to a subject in need thereof by controlling droplet size and deposit parameters of the medicament solution, the method comprising: (a) determining desired dosage of the medicament solution for the subject in need thereof; and (b) providing the desired dosage in a single application or multiple applications by determining the droplet size and deposit parameters.

Many factors, including those described herein, can influence the desired dosage. Once the desired dosage is determined, and also if desired frequency, such doses can be delivered. Frequency of dosing can vary by number of times, periodicity or both.

Also provided is a method for providing a solution to the eye, the method comprising: (a) providing droplets containing the solution, where the droplets have an average drop size in diameter and an average initial ejecting velocity; and (b) delivering the solution to the eye, where between about 80% to about 100% of the ejected mass of the droplets are deposited on the eye.

Further provided is a method of treating eye condition disorders, including glaucoma, infection or other eye indications, and related discomforts or other need in a subject in need thereof, the method comprising: (a) providing droplets containing said medicament with a specified average size and average initial ejecting velocity; and (b) delivering the medicament to the eye, where the droplets deliver a percentage of the ejected mass of the droplets to the eye.

Further provided is a method of providing a reduced dosage form of a medicament to an eye comprising: (a) providing droplets containing the medicament, where the droplets have an average drop size and an average initial ejecting velocity; and (b) delivering the medicament to the eye, where the droplets deliver a specified deposited mass of the droplets. In this or other aspects, the droplets can provide a total volume of less than 30 μl, 20 μl, 15 μl, 10 μl, 5 μl or 2 μl to eye.

Ejector Device

Exemplary ejector devices capable of generating droplets of the type described herein are provided in U.S. Patent Publication No. 2012/0143152, filed concurrently herewith, entitled Drop-Generating Device, herein incorporated by reference in its entirety. In one aspect of one such device an ejector plate is coupled to an actuator. The manner and location of attachment of the actuator to the plate affects the operation of the ejection assembly and the creation of the droplet stream with the option of the actuator being a piezoelectric actuator.

As described in U.S. Patent Publication No. 2012/0143152, again herein incorporated by reference in its entirety, the ejector device may generally be an ejector device for delivering a fluid to an eye of a subject. For instance, the ejector device may comprise: a housing; a reservoir disposed within the housing for receiving a volume of ophthalmic fluid; and an ejector mechanism configured to eject a stream of droplets to the eye of a subject upon activation of the device by a user. The ejected stream of droplets may have an average ejected droplet diameter greater than 15 microns and a low entrained airflow such that the ejected stream of droplets is deposited on the eye of the subject during use. In certain embodiments, the ejector device includes a piezoelectric ejector mechanism comprising an ejector plate having a first surface coupled to a fluid delivery area of the reservoir and including a plurality of openings formed through its thickness, and a piezoelectric actuator coupled to a second surface of the ejector plate, the piezoelectric actuator operable to oscillate the ejector plate at a frequency and generate the ejected stream of droplets.

Medicament and Other Compositions

Any medicament showing a desired ophthalmic activity may be administered. In an aspect, the medicament is available by prescription. In another aspect, the medicament is available over-the-counter. In an aspect, the medicament is or comprises a biologic agent. In an aspect, the biologic agent is selected from the group consisting of a full-length antibody, an active fragment of a full-length antibody, a peptide, a PEGylated peptide, and an enzymatic ingredient. In another aspect, the biologic ingredient is selected from the group consisting of bevacizumab, ranibizumab, FV fragments, bi-specific antibodies, fusion molecules, pegaptanib, plasmin and microplasmin. In a further aspect, the biologic agent is selected from the group consisting of ranibizumab antibody FAB (including LUCENTIS™), VEGF Trap fusion molecule (including VEGF Trap-Eye), microplasmin enzyme (including OCRIPLASMIN™), macugen pegylated polypeptide (including PEGAPTANIB™), and bevacizumab (including AVASTIN™).

In another aspect, a medicament to be administered is or comprises a small molecule. In an aspect, the medicament to be administered comprises a medicament selected from the group consisting of cyclosporine, neomycin, biomonidine, and aminoglycoside antibiotics, including, for example, tobramycin and gentamycin.

In various aspects, a solution may have different salinity. Salinity may be measured using a hydrometer. In various aspects, salinity may range from 0%, or a pure aqueous solution, to 2.5%. In other aspects, salinity may range from about 0.1% to about 1%, from about 0.5% to about 1%, from about 0.7% to about 1%, from about 0.8% to about 1%. In further aspects, salinity of a medicament may be about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, or about 1.5%. In other aspects, salinity may be less than about 1.5%, less than about 1%, less than about 0.5% or less than about 0.2%. In an aspect, the solution is isotonic with the site of delivery. For example, in various aspects, the medicament may be isotonic with human tears, blood, or eye tissue.

In an aspect, the medicament to be delivered comprises a medicament selected from the group consisting of carboxymethylcellulose sodium, tetrahydrozoline HCl, pheniramine maleate, ketotifen fumarate, oxymetazoline HCl, naphazoline HCl, pheniramine maleate, moxifloxacin hydrochloride, bromfenac, proparacaine hydrochloride, difluprednate, gatifloxacin, travoprost, bepotastine besilate, gatifloxacin, loteprednol etabonate, timolol ophthalmic, olopatadine hydrochloride, phenylephrine hydrochloride, levofloxacin, ketorolac tromethamine, letanoprost, bimatoprost and BAK free latanoprost. In another aspect, the medicament is selected from the group consisting of Refresh Tears™, Visine Advanced Relief™, Naphcon A™, Sensitive Eyes™, RENU®, Opti-free™ rewetting drops, Visine A.C.™, Hypo tears™, Alaway™, Visine L.R.™, Visine™ original, Rohto Cool™, Soothe XP™, Zaditor™, Bausch & Lomb Advanced Eye Relief Redness™, Visine A™, Opcon-A™, Walgreens artificial tears, Visine™ dry eye relief, Advanced Eye Relief Dry Eye™, Opti-free Replenish™, Clear Eyes™ redness relief, VIGAMOX®, Bromday™, Durezol™, ZYMAXID®, TRAVATAN Z®, tropicamide, BEPREVE™, Zymar™, LOTEMAX®, ISTALOL®, Pataday™, AK-Dilate™, TORADOL®, XALATAN®, and LUMIGAN®.

In another aspect, the medicament to be delivered comprises a medicament selected from the group consisting of fluorosilicone acrylate, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, tetrahydrozoline HCl, carboxymethylcellulose sodium, propylene glycol, hypromellose, zinc sulfate, dorzolamide HCl timolol maleate, azithromycin, brimonidine tartrate, nepafenac, brinzolamide, besifloxacin, dorzolamide HCl, prednisone acetate, loteprednol etabonate, tobramycin/dexamethasone, and cyclosporine. In a further aspect, the medicament is selected from the group consisting of Tears Naturale II™, Optimum NWN™, Thera Tears™, Systane Ultra™, GenTeal™, Systane Lubricant Eye Drops™, Blink™ tears, Visine Max Redness Relief™, Refresh Optive™, Muro128™, Systane Balance™, Rohto Hydra™, Rohto Ice™, Walgreens sterile artificial tears, Rohto Arctic™, Clear Eyes™ natural tears lubricant, SimilasanTM pink eye relief, Similasan™ allergy eye relief, Cosopt™, AzaSite™, Alphagan P™, Nevanac™, Azopt™, Besivance™, Trusopt™, Alrex™, and Restasis™.

In an aspect, an ophthalmic medicament to be delivered is used to treat glaucoma. In an aspect, a glaucoma medicament is selected from the group consisting of travoprost, timolol ophthalmic, latanoprost, bimatoprost, dorzolamide HCl, timolol maleate, brimonidine tartrate, brinzolamide, dorzolamide HCl, and BAK free latanoprost. In a further aspect, a medicament is selected from the group consisting of travoprost, timolol ophthalmic, latanoprost, bimatoprost, and BAK free latanoprost. In another aspect, a medicament is selected from the group consisting of dorzolamide HCl timolol maleate, brimonidine tartrate, brinzolamide, and dorzolamide HCl. In an aspect, a glaucoma medicament is selected from the group consisting of Travatan™, Istalol™, Xalatan™, Lumigan™, Cosopt™, Alphagan P™, Azopt™, and Trusopt™. In another aspect, a medicament is selected from the group consisting of Travatan™, Istolol™, Xalatan™, and Lumigan™. In a further aspect, a medicament is selected from the group consisting of Cosopt™, Alphagan P™, Azopt™, and Dorzolamide HCl™.

In an aspect, the concentration of an active ingredient in a medicament is measured as a percentage of the active ingredient in solution. In an aspect, the concentration of active ingredient ranges from about 0.0001% to about 5%. In another aspect, the concentration of active ingredient in a medicament ranges from about 0.0005% to about 1%. In other aspects, the concentration of active ingredient ranges from about 0.0005% to about 0.0001%, from about 0.0001% to about 0.001%, or from about 0.0005% to about 0.001%. In other aspects, the concentration of active ingredient ranges from about 0.005% to about 0.001% or from about 0.001% to about 0.01%. In another aspect, the concentration of active ingredient ranges from about 0.001% to about 0.5%. In various other aspects, the concentration of active ingredient is selected from the group consisting of about 0.0001%, about 0.0005%, about 0.001%, about 0.0025%, about 0.005%, about 0.01%, about 0.025%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, and about 5% measured as a percentage of the solution. However, given the lower dosing amounts afforded by the methods of the present disclosure, higher concentrations may be used depending on the intended use. For examples, about 10%, about 20%, about 25%, of the active ingredient in the medicament, measured as a percentage of the solution, may be utilized.

In an aspect, the medicament comprises a medicament selected from the group consisting of between about 0.02% and about 0.03% carboxymethylcellulose sodium, between about 0.4% and about 0.6% carboxymethylcellulose sodium, between about 0.04% and about 0.06% tetrahydrozoline HCl, between about 0.04% and about 0.06% tetrahydrozoline HCl, between about 0.24% and about 0.36% pheniramine maleate, between about 0.02% and about 0.03% ketotifen fumarate, between about 0.028% and about 0.042% ketotifen fumarate, between about 0.02% and about 0.03% oxymetazoline HCl, between about 0.0096% and about 0.0144% naphazoline HCl, between about 0.024% and about 0.036% naphazoline HCl, between about 0.24% and 0.36% pheniramine maleate, between about 0.4% and about 0.6% moxifloxacin hydrochloride, between about 0.072% and about 0.108% bromfenac, between about 0.4% and about 0.6% proparacaine hydrochloride, between about 0.04% and about 0.06% difluprednate, between about 0.4% and about 0.6% gatifloxacin, between about 0.0032% and about 0.0048% travoprost, between about 1.2% and about 1.8% bepotastine besilate, between about 0.24% and about 0.36% gatifloxacin, between about 0.4% and about 0.6% loteprednol etabonate, between about 0.4% and about 0.6% timolol ophthalmic, between about 0.16% and about 0.24% olopatadine hydrochloride, between about 2% and about 3% phenylephrine hydrochloride, between about 0.4% and about 0.6% levofloxacin, between about 0.32% and about 0.48% ketorolac tromethamine, between about 0.004% and about 0.006% letanoprost, and between about 0.024% and about 0.036% bimatoprost.

In an aspect, the medicament comprises a medicament selected from the group consisting of 0.025% carboxymethylcellulose sodium, 0.5% carboxymethylcellulose sodium, 0.05% tetrahydrozoline HCl, 0.5%, tetrahydrozoline HCl, 0.3% pheniramine maleate, 0.025% ketotifen fumarate, 0.035% ketotifen fumarate, 0.025% oxymetazoline HCl, 0.012% naphazoline HCl, 0.03% naphazoline HCl, 0.3% pheniramine maleate, 0.5% moxifloxacin hydrochloride, 0.09% bromfenac, 0.5% proparacaine hydrochloride, 0.05% difluprednate, 0.5% gatifloxacin, 0.004% travoprost, 1.5% bepotastine besilate, 0.3% gatifloxacin, 0.5% loteprednol etabonate,0.5% timolol ophthalmic, 0.2% olopatadine hydrochloride, 2.5% phenylephrine hydrochloride, 0.5% levofloxacin, 0.4% ketorolac tromethamine, 0.005% letanoprost, and 0.03% bimatoprost.

In another aspect, the medicament to be delivered comprises a medicament selected from the group consisting of between about 0.02% and about 0.3% sodium carboxymethylcellulose, between about 0.04% and about 0.06% tetrahydrozoline HCl, between about 0.4% and about 0.6% carboxymethylcellulose sodium, between about 0.48% and about 0.72% propylene glycol, between about 0.24% and about 0.36% hypromellose, between about 0.2% and about 0.3% zinc sulfate, between about 0.8% and about 1.2% azithromycin, between about 0.08% and about 0.12% brimonidine tartrate, between about 0.08% and about 0.12% nepafenac, between about 0.8% and about 1.2% brinzolamide, between about 0.48% and about 0.72% besifloxacin, between about 1.6% and about 2.4% dorzolamide HCl, between about 0.8% and about 1.2% prenisone acetate, between about 0.16% and about 0.24% loteprednol etabonate, between about 0.32% and about 0.48% tobramycin/dexamethasone, and between about 0.04% and about 0.06% cyclosporine.

In another aspect, the medicament to be delivered comprises a medicament selected from the group consisting of 0.025% sodium carboxymethylcellulose, 0.05% tetrahydrozoline HCl, 0.5% carboxymethylcellulose sodium, 0.6% propylene glycol, 0.3% hypromellose, 0.25% zinc sulfate, 1% azithromycin, 0.1% brimonidine tartrate, 0.1% nepafenac, 1% brinzolamide, 0.6% besifloxacin, 2% dorzolamide HCl, 1% prenisone acetate, 0.2% loteprednol etabonate, 0.4% tobramycin/dexamethasone, and 0.05% cyclosporine.

In an aspect, the medicament to be administered is not water-soluble. In another aspect, the medicament to be administered is poorly water-soluble. In a preferred aspect, the medicament is water-soluble, highly water-soluble, or very highly water-soluble. In an aspect, poorly water soluble is less than 10 ug/mL. In other aspects, water soluble is 10 to 60 ug/mL, highly water soluble is greater than 60 to 120 ug/mL, and very highly water soluble is greater than 120 ug/mL.

In another aspect, the medicament to be administered is formulated in an emulsion or a suspension. In an aspect, the medicament to be delivered comprises difluprednate or loteprednol etabonate. In an aspect, the medicament is Durezol™ or Lotemax™.

As generally understood by those skilled in the art, the listing of an active agent includes medicamently acceptable salts, esters, and acids thereof.

In an aspect, a medicament to be delivered comprises a preservative or other additive acceptable for use in the eye. In an aspect, a medicament comprises 20% or less of a preservative or other additive, or 15% or less, 12% or less, 10% or less, 8% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less of a preservative or other additive.

In another aspect, the medicament to be delivered comprises a polymeric ingredient. In an aspect, the medicament comprises an additive selected from the group consisting of glycerin, castor oil, carbomer, polyethylene glycol, and polysorbate 80. In an aspect, the concentration of polymer is measured as a percentage of the total solution by weight. In various aspects, the medicament comprises 10% or less of a polymer, 5% or less of a polymer, 4% or less of a polymer, 3% or less of a polymer, 2% or less of a polymer, 1.5% or less of a polymer, 1% or less of a polymer, 0.5% or less of a polymer, 0.4% or less of a polymer, 0.3% or less of a polymer, 0.2% or less of a polymer, 0.1% or less of a polymer, 0.05% or less of a polymer, or no detectable polymer. In various aspects, the medicament comprises 10% or less glycerin, 5% or less glycerin, 4% or less glycerin, 3% or less glycerin, 2% or less glycerin, 1.5% or less glycerin, 1% or less glycerin, 0.5% or less glycerin, 0.4% or less glycerin, 0.3% or less glycerin, 0.2% or less glycerin, 0.1% or less glycerin, 0.05% or less glycerin, or no glycerin.

In various aspects, the medicament may have different tonicity. Tonicity may be measured using a hydrometer. In various aspects, tonicity may range from 0%, or a pure aqueous solution, to 2.5%. In other aspects, tonicity may range from 0.1% to 1%, from 0.5% to 1%, from 0.7% to 1%, from 0.8% to 1%. In further aspects, tonicity of a medicament may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%. In an aspect, the medicament is isotonic with the site of delivery. For example, in various aspects, the medicament may be isotonic with human tears, blood, or eye tissue. It is contemplated that a solution with no active ingredient can be administered, e.g., a wetting agent.

In an aspect, the subject is less than 150 kilograms, 100 kilograms, less than 50 kilograms, less than 25 kilograms, or less than 10 kilograms. In this or other aspects, the subject may be less than 12 or 13 years old. In this or other aspects, the subject could be classified as human, male or female. In this or other aspects, the subject may be an agricultural animal. In this or other aspects, the subject may be non-human.

The viscosity of the medicament to be administered can vary. Viscosity of a medicament formulation can be measured by using a viscometer. In various aspects, viscosity of a medicament at 25 oC ranges from about 0.3 to about 300 cP, from about 0.3 to about 200 cP, from about 0.3 to about 100 cP, from about 0.3 to about 50 cP, from about 0.3 to about 40 cP, from about 0.3 to about 30 cP, from about 0.3 to about 20 cP, from about 0.3 to about 10 cP, from about 0.3 to about 5 cP, from about 0.3 to about 2 cP, from about 0.3 to about 1.5 cP, from about 0.3 to about 1 cP, from about 0.3 to about 0.9 cP, from about 0.3 to about 0.8 cP, from about 0.3 to about 0.7 cP from about 0.3 to about 0.6 cP, from about 0.3 to about 0.5 cP, or from about 0.3 to about 0.4 cP. In various other aspects, viscosity of a medicament to be administered is about 0.4 to about 1.4 cP, about 0.5 to about 1.3 cP, about 0.6 to about 1.2 cP, about 0.7 to about 1.1 cP, or about 0.8 to about 1.0 cP at room 25 oC. In various other aspects, viscosity of a medicament at 25 oC is about 0.3 cP, about 0.4 cP, about 0.5 cP, about 0.6 cP, about 0.7 cP, about 0.8 cP, about 0.9 cP, about 1 cP, about 1.1 cP, about 1.2 cP, about 1.3 cP, about 1.4 cP, or about 1.5 cP.

In some aspects, the active agents may exhibit increased stability and/or solubility at acid or alkaline pH and may be centrally administered in such form. In other aspects, a physiologically suitable pH (e.g., in the range of about pH 6.8-8.2, depending on the part of the eye) may be preferred for ophthalmic administration. However, titration to physiological pH may result in solubility and/or stability issues for many active agents. Therefore, it may be preferred in some cases to develop aqueous formulations in which the active agent is formulated with a solubility-enhancing agent or stabilizing excipients at a physiologically suitable pH. If titration is desired, any suitable buffer known in the medicament arts may be used (e.g., phosphate, acetate, glycine, citrate, imidazole, TRIS, MES, MOPS).

Further it may be desirable to maintain physiological isotonicity. For instance, in certain aspects, an osmolality ranging from about 100 to about 1000 mmol/kg, more particularly from about 280 to about 320 mmol/kg may be desired. Any suitable manner of adjusting tonicity known in the pharmaceutical arts may be used, e.g., adjustment with NaCl.

In accordance with certain aspects of the invention, medicament compositions are designed to maximize solubility and stability in ophthalmic applications and under conditions of use for administration to the eye.

Solubility Enhancing Agents

Again, in accordance with certain aspects of the invention, formulation active agents in aqueous solutions at physiological pH and tonicity are undertaken. However, to provide adequate solubility to the composition, the use of solubility enhancing agents may optionally be required.

Without intending to be limited by theory, in certain aspects, solubility enhancing agents may utilize their amphiphilic characteristics to increase the solubility of active agents in water. As generally understood by those skilled in the art, a wide variety of solubility enhancing agents that possess both nonpolar and hydrophilic moieties may be employed in connection with the present invention. However, amphiphilic agents possessing stronger hydrophobic character have the potential to interact with cell membranes and produce toxic effects. Therefore, again, without intending to be limited by theory, solubility enhancing agents with minimal hydrophobic character may be preferred in certain aspects within the context of the present invention, as such agents will be well-tolerated.

In addition to minimizing the hydrophobic character of the solubilizing agents employed, toxicity during administration may be reduced if the solubility enhancing agent is readily degraded in a cellular environment. The ability of cells to degrade compounds prevents their accumulation during chronic administration. To this end, the solubility enhancing agents may optionally include chemically-labile ester and ether linkages that contribute to low toxicity, and thereby prevent significant cellular accumulations during chronic administration.

In this regard, in accordance with certain aspects of the invention, the solubility-enhancing agent includes those that can be selected from cyclodextrins, e.g., β-hydroxypropyl-cyclodextrin, sulfobutyl-ether-β cyclodextrin, etc.

In other aspects, the solubility-enhancing agent may be selected from sucrose esters. Such agents are formed of two benign components (sucrose and fatty acids) linked by a highly labile ester bond. Although a readily-degradable linkage is beneficial from a toxicity standpoint, the solubility enhancing agent must be sufficiently robust to maintain its ability to solubilize the active agent during the desired conditions of use.

Generally, certain compositions of the invention may be prepared by formulating the desired amount, which may be a therapeutically-effective amount, of the desired active agent in a suitable solubility enhancing agent. Solubility enhancing agents include, but are not limited to, e.g., cyclodextrins, octylglucoside, pluronic F-68, Tween 20, sucrose esters, glycerol, ethylene glycol, alcohols, propylene glycol, carboxy methyl cellulose, solutol, mixtures thereof, etc. Other solubility-enhancing agents include, but are not limited to, polyethylene glycol (PEG), polyvinlypyrrolidone (PVP), arginine, proline, betaine, polyamino acids, peptides, nucleotides, sorbitol, sodium dodecylsulphate (SDS), sugar esters, other surfactants, other detergents and pluronics, and mixtures thereof Alternatively, stable multiphase systems could be employed to safely solubilize therapeutics for intrathecal delivery (e.g., liposomes, micro/nano emulsions, nanoparticles, dendrimers, micro/nano spheres).

Any suitable amount of solubility enhancing agent sufficient to solubilize the active agent of interest to the desired concentration may be used. In certain aspects, molar ratios of active agent to solubility-enhancing agent ranging from about 0.5:1 to about 1:10, particularly, about 1:1 to about 1:5, more particularly 1:1 to about 1:2, may be used to achieve adequate solubility of the active agent to the desired concentrations.

Stabilizing Excipients

In addition to solubility, the active agent must be sufficiently stable within the composition to withstand hydrolytic and oxidative degradation in order to maintain biological activity during administration. Active agents generally possesses the therapeutic effects observed during conventional administration; the stability of the medicament in the composition prior to central administration is also of importance. To this end, in certain aspects, the compositions of the present invention may further include stabilizing excipients and buffers acceptable for use in the eye.

Considering that oxidation represents a common degradation pathway, in certain aspects, the compositions of the invention may be deoxygenated (e.g., by saturating with nitrogen gas) to minimize the formation of reactive oxygen species that would degrade the active agent during storage. Another method would be to ensure that formulations are stored in a container that does not allow passage of light, thereby minimizing photo-induced degradation. In addition, in accordance with certain aspects of the invention, stabilizing excipients may optionally be used to, e.g., prevent or slow degradation by oxidation and/or hydrolysis of the active agents. For example, vitamin E, methionine, chelators and mannitol may be used to reduce oxidative degradation. Since the rates of many degradation reactions are pH-dependent, such formulations may include any suitable buffering agent known in the art (e.g., phosphate, acetate, glycine, citrate, imidazole, TRIS, MES, MOPS).

Stabilizing excipients useful in the context of the compositions described herein include any medicamently acceptable components which function to enhance the physical stability, and/or chemical stability of the active agent in the compositions of the invention. The medicament compositions described herein may include one or more stabilizing excipients, and each excipient may have one or more stabilizing functions.

In one aspect, the stabilizing excipient may function to stabilize the active agent against chemical degradation, e.g., oxidation, deamidation, deamination, or hydrolysis. In this regard, the stabilizing excipients may optionally be selected from antioxidants, such as ascorbic acid (vitamin C), vitamin E, tocopherol conjugates, tocopherol succinate, PEGylated tocopherol succinate, Tris salt of tocopherol succinate, Trolox, mannitol, sucrose, phytic acid, trimercaprol or glutathione.

The term “effective amount” refers to an amount of an active agent used to treat, ameliorate, prevent, or eliminate the identified ophthalmic condition (e.g., disease or disorder), or to exhibit a detectable therapeutic or preventative effect. The effect can be detected by, for example, chemical markers, antigen levels, or time to a measurable event, such as morbidity or mortality. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. Any of the agents can be provided in an effective amount.

For any active agent, the effective amount can be estimated initially either in cell culture assays, e.g., in animal models, such as rat or mouse models. An animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

To assist in understanding the present invention, the following Example is included. The experiments described herein should not, of course, be construed as specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the invention as described herein and hereinafter claimed.

U.S. patent application Ser. No. 13/184,484, filed Jul. 15, 2011, now U.S. Pat. No. 8,684,980, issued Apr. 1, 2014, entitled “Drop-Generating Device”, and U.S. patent application Ser. No. 13/184,468, filed Jul. 15, 2011, now U.S. Pat. No. 8,733,935, issued May 27, 2014, entitled “Method and System for Performing Remote Treatment and Monitoring” are also each herein incorporated by reference in their entireties.

EXAMPLE

Table A describes quantification of average droplet size and the maximum number of doses of various medications from individual eyedropper containers. Each experiment is repeated in three trials to calculate a more accurate average droplet size. By taking the volume of individual bottles and dividing it by the average droplet size, the maximum number of doses per eyedropper is calculated.

Column A contains the retail name of medications. In column B, the concentration of active ingredient of medication is listed as a percentage where publically available. Column C contains the name of preservative used in the medication, with column D displaying the percentage of the preservative in the solution. Column E is the manufacturer of the medication and column F is its classification as over-the counter (OTC) or by prescription (Rx). Columns G, H and I represent values from individual trials. The average in Column J is calculated using the values of G, H and I. Every bottle has a unique volume to contain a set amount of medication, which is noted in column K. The value in column K is divided by the average in column J to determine the number of doses possible as noted in Column L.

TABLE A Preserv med in in Bottle solution solution RX/ Size Name (%) (%) (%) Company OTC Trial 1 Trial 2 Trial 3 Avg (ml) Doses Blink tears Sodium Advanced OTC 0.041 0.046 0.041 0.0427 15 352 Chlorate Medical Optics thera tears (sodium 0.025 Sodium Advanced OTC 0.046 0.05 0.049 0.0483 30 621 carboxymethylcellulose) Perborate Vision Research Naphcon A 0.3 Benzalkonium 0.01 Alcon OTC 0.038 0.04 0.04 0.0393 15 381 (Pheniramine Chloride Maleate) Opti-free express Polyquad Alcon OTC 0.036 0.038 0.038 0.037333 20 535.7 rewetting drops Opti-free Replenish Polyquad 0.001 Alcon OTC 0.026 0.027 0.029 0.0273 10 366 Systane Balance 0.6 Polyquad 0.001 Alcon OTC 0.039 0.035 0.035 0.0363 10 275 (propylene glycol) Systane Lubricant Polyquad Alcon OTC 0.038 0.044 0.05 0.0440 15 341 Eye drops Systane ultra Polyquad 0.001 Alcon OTC 0.047 0.047 0.049 0.0477 10 210 Tears Naturale II Polyquad 0.001 Alcon OTC 0.057 0.056 0.06 0.0577 15 260 Refresh optive 0.5 PURITE Allergan OTC 0.04 0.041 0.04 0.0403 15 372 (Carboxymethylcellulose Sodium) Refresh Tears 0.5 PURITE Allergan OTC 0.054 0.055 0.059 0.0560 15 268 (Carboxymethylcellulose Sodium) Adv. Eye Relief Dry Benzalkonium 0.01 Bausch & OTC 0.027 0.028 0.03 0.0283 15 529 Eye Chloride Lomb Adv. Eye relief 0.03 Benzalkonium 0.01 Bausch & OTC 0.032 0.031 0.032 0.0317 15 474 Redness (Naphazoline Chloride Lomb HCl) Alaway (ketotifen 0.035 Benzalkonium 0.01 Bausch & OTC 0.036 0.034 0.035 0.0350 10 286 fumarate) Chloride Lomb Muro 128 Bausch & OTC 0.038 0.041 0.038 0.0390 15 385 Lomb Opcon-A Benzalkonium Bausch & OTC 0.028 0.031 0.032 0.0303 15 495 Chloride Lomb Renu Sorbic acid, 0.15 and Bausch & OTC 0.036 0.039 0.041 0.0387 15 388 Disodium edetate .1 Lomb Sensitive eyes Sorbic Acid and .1 and Bausch & OTC 0.039 0.038 0.04 0.0390 30 769 Disodium edetate .025 Lomb Soothe xp polyhexamethyle Bausch & OTC 0.033 0.033 0.033 0.0330 15 455 ne biguanide Lomb Visine A.C. 0.05 Benzalkonium Johnson & OTC 0.036 0.036 0.038 0.0367 15 409 (Tetrahydrozoline Chloride Johnson HCl) Visine Advanced 0.05 Benzalkonium Johnson & OTC 0.038 0.043 0.041 0.0407 19 467 Relief Chloride Johnson (Tetrahydrozoline HCl) Visine Dry eye relief Benzalkonium 0.01 Johnson & OTC 0.031 0.03 0.027 0.0293 15 511 Chloride Johnson Visine L.R. Long 0.025 Benzalkonium Johnson & OTC 0.036 0.036 0.032 0.0347 15 433 Lasting Redness Chloride Johnson Relief (Oxymetazoline HCl) Visine Max Redness 0.05 Benzalkonium Johnson & OTC 0.04 0.042 0.042 0.0413 15 363 Relief Chloride Johnson (Tetrahydrozoline HCl) Visine original 0.05 Benzalkonium Johnson & OTC 0.034 0.034 0.034 0.0340 19 559 (Tetrahydrozoline Chloride Johnson HCl) Visine-A 0.3 Benzalkonium 0.01 Johnson & OTC 0.031 0.031 0.033 0.0317 15 474 (Pheniramine Chloride Johnson Maleate) Optimum WRW Benzyl Alcohol, .1, .05, Lobob OTC 0.055 0.052 0.058 0.055 30 545.5 (fluoro silicone Sorbic Acid, .1 acrylate) Disodium edetate Clear eyes natural Benzalkonium MedTech OTC 0.026 0.03 0.024 0.0267 15 563 tears lubricant Chloride Products Clear eyes Redness 0.012 Benzalkonium MedTech OTC 0.024 0.02 0.021 0.0217 30 1385 relief (naphazoline Chloride Products HCl) GenTeal GenAqua Novartis OTC 0.046 0.046 0.047 0.0463 15 324 (hydroxypropyl (Sodium methylcellulose) perborate) Hypo tears Benzalkonium 0.01 Novartis OTC 0.032 0.039 0.038 0.0363 30 826 Chloride Zaditor (ketotifen 0.025 Benzalkonium 0.01 Novartis OTC 0.033 0.032 0.034 0.0330 5 152 fumarate) Chloride Rohto arctic 0.05 Rohto OTC 0.035 0.03 0.034 0.0330 13 394 (Tetrahydrozoline HCl) Rohto Cool 0.012 Benzalkonium Rohto OTC 0.037 0.033 0.03 0.0333 13 390 (naphazoline HQ) Chloride Rohto Hydra 0.3 Rohto OTC 0.041 0.034 0.03 0.0350 13 371 (hypromellose) Rohto ice (Zinc 0.25 Rohto OTC 0.035 0.03 0.038 0.0343 13 379 Sulfate) Similasan allergy eye Silver sulphate Similasan OTC 0.044 0.044 0.046 0.0447 10 224 relief Similasan pink eye Silver sulphate Similasan OTC 0.048 0.045 0.048 0.0470 10 213 relief Walgreens artificial Benzalkonium 0.01 Walgreens OTC 0.028 0.03 0.032 0.0300 30 1000 tears Chloride Walgreens sterile None 0 Walgreens OTC 0.031 0.033 0.036 0.0333 32 artificial tears (ampules) AK-Dilate 2.5 Benzalkonium 0.01 Akorn Rx 0.023 0.029 0.029 0.0270 15 556 Phenylephrine Chloride Hydrochloride Azopt (brinzolamide) 1 Benzalkonium 0.01 Alcon Rx 0.039 0.039 0.039 0.0390 10 256 Chloride Nevanac (nepafenac) 0.1 Benzalkonium 0.005 Alcon Rx 0.04 0.039 0.043 0.0407 3 74 Chloride Pataday (olopatadine 0.2 Benzalkonium 0.01 Alcon Rx 0.028 0.029 0.027 0.0280 2.5 89 hydrochloride) Chloride Travatan 0.004 Sofzia Alcon Rx 0.03 0.034 0.034 0.0327 5 153 Z(travoprost) vigamox 0.5 None 0 Alcon Rx 0.039 0.045 0.046 0.0433 3 69 (moxifloxacin hydrochloride) Ketorolac 0.4 Benzalkonium 0.006 Alcon- Rx 0.025 0.026 0.024 0.0250 5 200 Tromethamine Chloride Falcon Prednisolone Acetate 1 Benzalkonium 0.01 Alcon- Rx 0.03 0.033 0.037 0.0333 5 150 Ophthalmic Chloride Falcon suspension Proparacaine 0.5 Benzalkonium 0.01 Alcon- Rx 0.036 0.04 0.042 0.0393 15 381 Hydrochloride Chloride Falcon Ophthalmic solution Tobramycin and 0.4 Benzalkonium 0.01 Alcon- Rx 0.032 0.033 0.029 0.0313 5 160 Dexamethasone Chloride Falcon Tropicamide 1 Benzalkonium 0.01 Alcon- Rx 0.033 0.028 0.034 0.0317 15 474 Chloride Falcon Alphagan P 0.1 PURITE 0.005 Allergan Rx 0.041 0.042 0.05 0.0443 5 113 (brimonidine tartrate) Lumigan 0.03 Benzalkonium 0.005 Allergan Rx 0.025 0.021 0.022 0.0227 5 221 (bimatoprost) Chloride Restasis 0.05 None (Sterile) 0 Allergan Rx 0.025 0.023 0.025 0.0243 30 (cyclosporine) (ampules) Zymar (gatifloxacin) 0.3 Benzalkonium 0.005 Allergan Rx 0.029 0.031 0.031 0.0303 5 165 Chloride Zymaxid 0.5 Benzalkonium 0.005 Allergan Rx 0.033 0.035 0.032 0.0333 2.5 75 (gatifloxacin) Chloride Alrex (loteprednol 0.2 Benzalkonium 0.01 Bausch & Rx 0.032 0.034 0.033 0.0330 5 152 etabonate) Chloride Lomb Bepreve (bepotastine 1.5 Benzalkonium 0.005 Bausch & Rx 0.031 0.033 0.03 0.0313 5 160 besilate) Chloride Lomb Besivance 0.6 Benzalkonium 0.01 Bausch & Rx 0.036 0.041 0.04 0.0390 5 128 (besifloxacin) Chloride Lomb Lotemax (loteprednol 0.5 Benzalkonium 0.01 Bausch & Rx 0.029 0.031 0.031 0.0303 5 165 etabonate) Chloride Lomb Dorzolamide HCl Benzalkonium 0.0075 Hi-tech Rx 0.051 0.048 0.053 0.0507 10 197 Timolol Maleate Chloride AzaSite 1 Benzalkonium 0.003 Inspire Rx 0.046 0.045 0.051 0.0473 2.5 53 (azithromycin) Chloride Bromday (bromfenac) 0.09 Benzalkonium Ista Rx 0.046 0.04 0.038 0.0413 1.7 41 Chloride Levofloxacin 0.5 Benzalkonium 0.005 Pack Rx 0.028 0.027 0.025 0.0267 5 188 Chloride Xalatan (latanoprost) 0.005 Benzalkonium 0.02 Pfizer Rx 0.022 0.023 0.026 0.0237 2.5 106 Chloride Istalol 0.5 Benzalkonium 0.005 Senju Rx 0.026 0.031 0.031 0.0293 5 170 Chloride Durezol 0.05 Sorbic Acid 0.1 Sirion Rx 0.04 0.039 0.034 0.0377 5 133 (difluprednate) Therapeutics Dorzolamide HCl 2 Benzalkonium 0.0075 Leva Rx 0.036 0.04 0.04 0.0387 10 259 Chloride BAK free Latanoprost 0.035 0.033 0.034 0.0340 

1-53. (canceled)
 53. A method of delivering droplets to an eye of a subject in need thereof, the method comprising: (a) generating the droplets via a piezoelectric actuated ejection device, wherein: (i) the droplets comprise a medicament, (ii) the droplets have a total volume of less than 15 μl; and (ii) the piezoelectric actuated ejection device comprises a housing; a reservoir containing a composition disposed within the housing; and an ejector mechanism fluidly coupled to the reservoir, the ejector mechanism comprising an ejector plate comprising a plurality of openings formed through its thickness, and a piezoelectric actuator coupled to the ejector plate, the actuator being operable to oscillate the ejector plate at a frequency to generate the droplets from the composition upon actuation; (b) delivering the droplets to the eye of the subject.
 54. The method of claim 53, wherein the droplets have a total volume of less than 10 μl.
 55. The method of claim 53, wherein the droplets have a total volume of 5 μl to less than 15 μl.
 56. The method of claim 53, wherein the droplets have a total volume of 5 μl to less than 10 μl.
 57. The method of claim 53, wherein the droplets have an average droplet size from about 15 microns to about 100 microns
 58. The method of claim 57, wherein the droplets have an average droplet size from about 20 microns to about 100 microns.
 59. The method of claim 53, wherein the droplets have a total volume of less than 10 μl and an average droplet size from about 15 microns to about 100 microns.
 60. The method of claim 59, wherein the droplets have an average droplet size from about 20 microns to about 80 microns.
 61. The method of claim 53, wherein the droplets have an average initial ejecting velocity from about 1 m/s to about 10 m/s.
 62. A method of delivering droplets to an eye of a subject in need thereof, the method comprising: (a) generating the droplets via a piezoelectric actuated ejection device, wherein: (i) the droplets comprise a medicament, (ii) the droplets have an average droplet size from about 15 microns to about 100 microns; and (ii) the piezoelectric actuated ejection device comprises a housing; a reservoir containing a composition disposed within the housing; and an ejector mechanism fluidly coupled to the reservoir, the ejector mechanism comprising an ejector plate comprising a plurality of openings formed through its thickness, and a piezoelectric actuator coupled to the ejector plate, the actuator being operable to oscillate the ejector plate at a frequency to generate the droplets from the composition upon actuation; (b) delivering the droplets to the eye of the subject.
 63. The method of claim 62, wherein the droplets have an average droplet size from about 20 microns to about 100 microns.
 64. The method of claim 62, wherein the droplets have an average droplet size from about 20 microns to about 80 microns.
 65. The method of claim 62, wherein the droplets have a total volume of less than 10 μl.
 66. The method of claim 65, wherein the droplets have a total volume of 5 μl to less than 10 μl.
 67. The method of claim 62, wherein the droplets have a total volume of less than 10 μl and an average droplet size from about 20 microns to about 100 microns.
 68. The method of claim 67, wherein the droplets have an average initial ejecting velocity from about 1 m/s to about 10 m/s.
 69. The method of claim 53, wherein the medicament comprises tropicamide and phenylephrine hydrochloride.
 70. The method of claim 53, wherein the medicament comprises artificial tears, tropicamide bevacizumab, ranibizumab, pegaptanib, plasmin, microplasmin, cyclosporine, neomycin, tobramycin, gentamycin, carboxymethylcellulose sodium, tetrahydrozoline hydrochloride, pheniramine maleate, ketotifen fumarate, oxymetazoline hydrochloride, naphazoline hydrochloride, pheniramine maleate, moxifloxacin hydrochloride, bromfenac, proparacaine hydrochloride, difluprednate, gatifloxacin, travoprost, bepotastine besilate, gatifloxacin, loteprednol etabonate, timolol, olopatadine hydrochloride, phenylephrine hydrochloride, levofloxacin, ketorolac tromethamine, latanoprost, fluorosilicone acrylate, dorzolamide hydrochloride, azithromycin, brimonidine tartrate, nepafenac, brinzolamide, besifloxacin, prednisone acetate, or dexamethasone.
 71. The method of claim 62, wherein the medicament comprises tropicamide and phenylephrine hydrochloride.
 72. The method of claim 62, wherein the medicament comprises artificial tears, tropicamide bevacizumab, ranibizumab, pegaptanib, plasmin, microplasmin, cyclosporine, neomycin, tobramycin, gentamycin, carboxymethylcellulose sodium, tetrahydrozoline hydrochloride, pheniramine maleate, ketotifen fumarate, oxymetazoline hydrochloride, naphazoline hydrochloride, pheniramine maleate, moxifloxacin hydrochloride, bromfenac, proparacaine hydrochloride, difluprednate, gatifloxacin, travoprost, bepotastine besilate, gatifloxacin, loteprednol etabonate, timolol, olopatadine hydrochloride, phenylephrine hydrochloride, levofloxacin, ketorolac tromethamine, latanoprost, fluorosilicone acrylate, dorzolamide hydrochloride, azithromycin, brimonidine tartrate, nepafenac, brinzolamide, besifloxacin, prednisone acetate, or dexamethasone. 